TLR signaling controls multiple pathways for tolerating the commensal microbiota.

<p>Crosstalk between the immune system and the microbiota can limit disease in three non-mutually exclusive ways; by limiting the migration of microbes into sensitive host tissues by promoting healthy barrier function (i.e. spatial segregation), by changing the community of organisms that colonize the host (some may be disease protective while others may be disease inductive), and by educating the immune system to be tolerant of innocuous members of the microbial community. (A) Intestinal epithelial cells are the first cells to come into contact with luminal bacteria. Multiple studies have demonstrated that a mechanism to avoid overt inflammation toward the intestinal bacteria is to sequester TLRs toward the basal compartment of the IEC. Therefore, TLRs, and subsequently inflammation, are only engaged when bacteria have penetrated host tissue. This represents a passive mechanism to avoid chronic inflammation. (B) Spatial segregation of the commensal microbiota is another mechanism to avoid inflammation within the intestine. A thick, organized mucus layer that is composed of anti-bacterial proteins, mucins, and antibodies creates a barrier between the host tissue and the luminal bacteria. (C) Several examples exist that demonstrate how TLR signaling can influence the diversity of the microbial community. Additionally, a single commensal species, <i>B. fragilis</i>, has been shown to utilize TLR2 signaling to colonize the host tissue. Therefore, a mutation in any one of the TLRs could lead to a loss of colonization by a beneficial commensal and a change in the structure of the microbial community. Changes in microbial community dynamics could lead to a loss of tolerance within the intestine. (D) It is now becoming appreciated that cells of both the innate and adaptive immune system have functional TLR receptors. TLR signaling on various cell types can have differential functional consequences. Indeed, while triggering of TLR signaling on macrophages has long been known to induce inflammation, it was just recently demonstrated that B cell-intrinsic TLR signaling is important for maintaining tolerance within the intestine. Therefore, TLRs represent a way in which the commensal microbiota can communicate with the host and loss of this machinery could disrupt intestinal tolerance.</p

Data from: Experimental manipulation of population-level MHC diversity controls pathogen virulence evolution in Mus musculus

The virulence levels attained by serial passage of pathogens through similar host genotypes are much higher than observed in natural systems, however, it is unknown what keeps natural virulence levels below these empirically demonstrated maximum levels. One hypothesis suggests that host diversity impedes pathogen virulence, because adaptation to one host genotype carries tradeoffs in the ability to replicate and cause disease in other host genotypes. To test this hypothesis, with the simplest level of population diversity within the loci of the major histocompatibility complex (MHC), we serially passaged Friend Virus Complex (FVC) through two rounds, in hosts with either the same MHC genotypes (pure passage) or hosts with different MHC genotypes (alternated passage). Alternated passages showed a significant overall reduction of viral titer (31%) and virulence (54%) when compared to pure passages. Furthermore, a resistant host genotype initially dominated any effects due to MHC diversity, however, when FVC was allowed to adapt to the resistant host genotype, predicted MHC effects emerged, i.e. alternated lines show reduced virulence. These data indicate serial exposure to diverse MHC genotypes is an impediment to pathogen adaptation, suggesting genetic variation at MHC loci is important for limiting virulence in a rapidly evolving pathogen and supports negative frequency-dependent selection as a force maintaining MHC diversity in host populations

MyD88 Signaling in T Cells Directs IgA-Mediated Control of the Microbiota to Promote Health

SummaryAltered commensal communities are associated with human disease. IgA mediates intestinal homeostasis and regulates microbiota composition. Intestinal IgA is produced at high levels as a result of T follicular helper cell (TFH) and B cell interactions in germinal centers. However, the pathways directing host IgA responses toward the microbiota remain unknown. Here, we report that signaling through the innate adaptor MyD88 in gut T cells coordinates germinal center responses, including TFH and IgA+ B cell development. TFH development is deficient in germ-free mice and can be restored by feeding TLR2 agonists that activate T cell-intrinsic MyD88 signaling. Loss of this pathway diminishes high-affinity IgA targeting of the microbiota and fails to control the bacterial community, leading to worsened disease. Our findings identify that T cells converge innate and adaptive immune signals to coordinate IgA against the microbiota, constraining microbial community membership to promote symbiosis

Microbiota promotes systemic T-cell survival through suppression of an apoptotic factor

Symbiotic microbes impact the severity of a variety of diseases through regulation of T-cell development. However, little is known regarding the molecular mechanisms by which this is accomplished. Here we report that a secreted factor, Erdr1, is regulated by the microbiota to control T-cell apoptosis. Erdr1 expression was identified by transcriptome analysis to be elevated in splenic T cells from germfree and antibiotic-treated mice. Suppression of Erdr1 depends on detection of circulating microbial products by Toll-like receptors on T cells, and this regulation is conserved in human T cells. Erdr1 was found to function as an autocrine factor to induce apoptosis through caspase 3. Consistent with elevated levels of Erdr1, germfree mice have increased splenic T-cell apoptosis. RNA sequencing of Erdr1-overexpressing cells identified the up-regulation of genes involved in Fas-mediated cell death, and Erdr1 fails to induce apoptosis in Fas-deficient cells. Importantly, forced changes in Erdr1 expression levels dictate the survival of auto-reactive T cells and the clinical outcome of neuro-inflammatory autoimmune disease. Cellular survival is a fundamental feature regulating appropriate immune responses. We have identified a mechanism whereby the host integrates signals from the microbiota to control T-cell apoptosis, making regulation of Erdr1 a potential therapeutic target for autoimmune disease